tbuckley/cabot-search huggingface dataset:
OUTC-09. PEDIATRIC LOW GRADE GLIOMA SURVIVORS’ NEED FOR SURVIVORSHIP CARE: ‘ENGAGE’ A MULTIDISCIPLINARY, E-HEALTH INTERVENTION
Authors: Jordana McLoone, Mashaal Hamayun, Sumanth Nagabushan, Christina Signorelli, Claire Wakefield, Karen Johnston, Rachael Bell, Richard Cohn
Journal: Neuro-Oncology (2023)

Abstract Higher survival rates for children diagnosed with low-grade gliomas (LGG), compared to other brain cancers, often limit the survivorship resources afforded this cohort, despite potential long-term physical, functional and psychological impacts. We conducted a two-phase program of research, first evaluating LGG survivors’ need for support during the survivorship phase, followed by the development and pilot evaluation of a multidisciplinary, telehealth, survivorship program. Phase 1: We conducted a retrospective cohort study of children aged 0-16 years at diagnosis, diagnosed between 2000-2015, assessing psychosocial impact and quality of life. Phase 2: We developed ‘Engage Brain’, a multidisciplinary, telehealth program, designed to improve medical and psychosocial outcomes for childhood cancer survivors throughout their lifespan. Key components of Engage’s design include distance-delivered care to ensure access for all survivors irrespective of whether they live close to a tertiary, survivorship center; hospital-based expertise integrated with local, primary care services to ensure a model of care which is sustainable long-term; nurse-led care providing tailored education to encourage adoption of a prevention-focused healthy lifestyle to mitigate survivors’ personal risk and reduce ongoing costs to the individual and healthcare system; psychosocial focus, incorporating allied health staff (psychologist/social worker) as an integral aspect of care. Phase 1: 45 survivors participated (36% female, mean age 14.8 years, average 7.5 years post-treatment). Survivors reported high levels of anxiety (23%), depression (14%), fatigue (62%). Phase 2: 30 LGG survivors completed Engage Brain intervention (50% female, mean age 21 years, average 11.5 years post-treatment). 64% uptake, 10% attrition. Most (78%) of participants ‘agree’-‘greatly agree’ that Engage Brain provides ‘high-quality survivorship care’ and ‘help accessing survivorship care’. This program of research illustrates the long-term needs of LGG survivors, despite their lower risk status compared to other brain cancers, and the feasibility of providing a multidisciplinary, telehealth intervention to support them.
METB-01. EXTRACHROMOSOMAL DNA IS ASSOCIATED WITH ONCOGENE AMPLIFICATION AND POOR SURVIVAL ACROSS MULTIPLE PEDIATRIC CANCER TYPES
Authors: Sunita Sridhar, Owen Chapman, Aditi Dutta, Shanqing Wang, Lukas Chavez
Journal: Neuro-Oncology (2023)

Abstract Circular extrachromosomal DNA (ecDNA) is an important driver of aggressive cancers. Its frequency and impact on the spectrum of pediatric cancers has yet to be fully described. To determine the ecDNA prevalence in various pediatric cancer types, we accessed whole genome sequencing (WGS) data in the Children’s Brain Tumor Network (CBTN) and St. Jude cancer cloud genomics platforms and utilized the bioinformatics tools Amplicon Architect (AA) and Amplicon Classifier (AC) to reconstruct ecDNA sequence structures. We then identified which genes were amplified on the ecDNA and the association of ecDNA with survival using Kaplan Meier curves. In total, we analyzed a retrospective cohort of over 1600 tumor biopsies from 1400 different patients, spanning 69 different tumor types. We identified ecDNA in 14 tumor types. The incidence of ecDNA within these 14 tumors was 16% with the highest percentage in osteosarcoma (47%), pineoblastoma (40%) and rhabdomyosarcoma (40%). The overall incidence of ecDNA across the patient cohort was 10%. In analyzing matched diagnostic/relapse and relapse/progression pairs, ecDNA was noted to evolve over time with progression of disease. Across the cohort, ecDNA was found to be significantly associated with poor survival. Our preliminary results demonstrate that ecDNA is prevalent in pediatric cancer, can contain known and potentially novel oncogenes and can be associated with poorer outcomes across many different pediatric cancer types.
SURG-02. MAGNETIC RESONANCE-GUIDED HIGH-INTENSITY FOCUSED ULTRASOUND (MRGHIFU) FOR TREATMENT OF LOW GRADE GLIOMA IN A PEDIATRIC PATIENT
Authors: Kelsi Chesney, Nirali Patel, Gregory Keating, Roger Packer, Robert Keating
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Transcranial magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) has demonstrated efficacy in the treatment of adult essential tremor through targeted thermoablation visualized in real-time with MR thermography. The minimally invasive nature of MRgHIFU and lack of ionizing radiation makes it an appealing treatment modality for pediatric patients. There is limited data describing MRgHIFU for pediatric brain tumors. This case report describes the use of MRgHIFU to treat a low grade glioma in a pediatric patient. METHODS A prospective, non-randomized, single-arm study enrolled patients 8-22 years old with benign intracranial tumors requiring intervention to be treated with the ExAblate 4000 System. Clinical and radiographic examinations were performed at the following intervals after treatment: 1 day, 14 days, 3 months, 6 months, and 1 year. RESULTS One patient was treated with MRgHIFU in 2022. A 12 year-old female with headaches and Neurofibromatosis Type 1 (NF1) without prior medical or surgical treatment presented with a progressive enhancing lesion in the right parieto-occipital region. Stereotactic biopsy confirmed pathological diagnosis of a low-grade glioma. MRgHIFU was used to treat the lesion with 5 sonications ranging 600-800 watts resulting in immediate T2 and FLAIR changes. There were no complications or adverse events. MRI demonstrated slight volume reduction after one year. The patient scored herself a 7 on the Patient Global Impression of Change scale for considerable improvement. Her headaches improved and she participates actively in school and sports. CONCLUSION MRgHIFU is an attractive alternative to open craniotomy and/or radiation for pediatric patients with benign brain tumors. In our experience with one patient, the use of MRgHIFU for treatment of a low-grade glioma demonstrated safety in addition to radiographic disease control at 1 year with favorable patient impression scores. Additional patient enrollment and extended follow-up time will be necessary to determine generalizability and therapeutic longevity.
TRLS-13. NOVEL PAN-RAF INHIBITOR BELVARAFENIB AS A PROMISING TARGETED THERAPY FOR BRAF-ALTERED PEDIATRIC LOW-GRADE GLIOMAS
Authors: Maxine Gonzalez, Brittany Lebert, Stephani Campion, Ana Aguilar-Bonilla, Amy Smith
Journal: Neuro-Oncology (2023)

Abstract In recent years targeted therapy has improved the outcome of childhood cancer patients. The second most common pediatric cancers are central nervous system (CNS) tumors, particularly low-grade gliomas (LGGs). Approximately 15-20% of pediatric LGGs cases present with oncogenic mutations that alter the RAS/mitogen-activated protein kinase (MAPK) signaling pathway by the B-RAF kinase constitutive activation. Only five RAF inhibitors are FDA-approved as cancer treatments and with limited-to-no data for pediatric patients. The lack of pediatric data results from limited access to childhood clinical trials, although there has been an increase in clinical trials for RAF inhibitors and combinations for children. However, there is a pressing need for alternative therapeutic approaches for pediatric patients with BRAF-altered LGGs. Hence, this study proposes a type II pan-RAF inhibitor called Belvarafenib (BEV) as a potential therapeutic candidate. Belvarafenib has shown viability effects at 500fM to 5nM in a PRKAR2B/BRAF fusion patient-derived cell line with a calculated cytotoxic concentration 50 (CC50) of 2nM. The expression of apoptotic markers will be measured to characterize the mechanism of cell death through BEV’s direct stimulation of the MAPK signaling or via an alternative pathway. Understanding the allosteric properties of the RAF inhibitor Belvarafenib enables the opportunity to have effective and well-tolerated alternative therapies for BRAF-altered tumors in children. Thus, this preliminary study intends to profile the effectivity of Belvarafenib in cell culture and help design in vivo experiments with the potential to establish clinical trials in combination with other potential therapeutic agents.
A subpopulation of CD146+ macrophages enhances antitumor immunity by activating the NLRP3 inflammasome
Authors: Lin Jing, Yunhe An, Tanxi Cai, Jianquan Xiang, Baoming Li, Jiang Guo, Xinran Ma, Ling Wei, Yanjie Tian, Xiaoyan Cheng, Xuehui Chen, Zheng Liu, Jing Feng, Fuquan Yang, Xiyun Yan, Hongxia Duan
Journal: Cellular and Molecular Immunology (2023)

Abstract As one of the main tumor-infiltrating immune cell types, tumor-associated macrophages (TAMs) determine the efficacy of immunotherapy. However, limited knowledge about their phenotypically and functionally heterogeneous nature restricts their application in tumor immunotherapy. In this study, we identified a subpopulation of CD146 + TAMs that exerted antitumor activity in both human samples and animal models. CD146 expression in TAMs was negatively controlled by STAT3 signaling. Reducing this population of TAMs promoted tumor development by facilitating myeloid-derived suppressor cell recruitment via activation of JNK signaling. Interestingly, CD146 was involved in the NLRP3 inflammasome-mediated activation of macrophages in the tumor microenvironment, partially by inhibiting transmembrane protein 176B (TMEM176B), an immunoregulatory cation channel. Treatment with a TMEM176B inhibitor enhanced the antitumor activity of CD146 + TAMs. These data reveal a crucial antitumor role of CD146 + TAMs and highlight the promising immunotherapeutic approach of inhibiting CD146 and TMEM176B.
MDB-39. ASSESSMENT OF MEDULLOBLASTOMA PATIENTS THROUGH MONITORING EXTRACELLULAR VESICLES VIA SURFACE-ENHANCED RAMAN SPECTROSCOPY COMBINED WITH MACHINE LEARNING
Authors: Carolina del Real Mata, Yao Lu, Mahsa Jalali, Laura Montermini, Marjan Khatami, Geoffroy Danieau, Ana Castillo Orozco, Janusz Rak, Livia Garzia, Sara Mahshid
Journal: Neuro-Oncology (2023)

Abstract Medulloblastoma (MB) is the most common brain pediatric tumor associated with considerable morbidity. While MB is treated with multimodal approaches, including surgery, the currently available technologies fail to provide non-invasive access for continuous assessment of disease progression and therapy efficacy. There is a need to develop monitoring systems for frequent use with minimum invasiveness that provides actionable information incorporating the heterogeneous nature of MB. Liquid biopsy is a non-invasive approach using circulating biomarkers, including nano-sized extracellular vesicles (EVs). EVs are secreted by all cells, even cancerous ones. Molecular composition of cancer EVs contains fingerprints of their parental cell, reflective of salient features of the underlying disease. We used 54 pediatric plasma samples of MB patients to determine feasibility of assessing disease progression through EVs analysis. EVs were isolated from plasma using size exclusion chromatography prior to loading onto unique MoSERS chip. MoSERS platform contains nanostructured capture element for single EV detection capable of profiling liquid biopsy samples for surface-enhanced Raman Spectroscopy. A total of 54 datasets were generated, each comprised of EV spectra collected with the MoSERS chip at a single EV resolution. A spectral library was integrated with the datasets of patients with confirmed MB diagnosis (n=34) and healthy controls (n=20), required to train and test a machine-learning implementation. The combination of MoSERS with robust machine learning algorithm provides a strong analysis and a simple interpretation of the patient’s health status. We optimized a pipeline for the data collection and analysis, demonstrating the feasibility of the MoSERS platform for pediatric cancer indication and need for less than 10 μl of sample to generate each unique dataset. Preliminary results demonstrate that MoSERS performance correlates with the results of clinical standards, providing a proof-of-concept for its implementation as a non-invasive and accessible alternative to monitor the health status of MB patients.
MDB-03. DFMO AS A TREATMENT STRATEGY IN GROUP 3 MEDULLOBLASTOMA
Authors: Shubin Shahab, Christianna Roggeveen, Tobey MacDonald, Anna Kenney
Journal: Neuro-Oncology (2023)

Abstract Medulloblastomas, the most common malignant brain tumor in children, are subdivided into 4 major molecular subgroups. Among these, Group 3 medulloblastomas have one of the worst prognoses. We have recently identified the LIN28B pathway as being critically important in Group 3 medulloblastoma growth in vitro and in vivo. There are few targeted inhibitors of the LIN28B pathway and none are currently in clinical practice. Recently DFMO has been identified as an indirect inhibitor of the LIN28B-let-7 axis through its inhibition of polyamine biosynthesis. Another recent study identified ornithine, a precursor to polyamines, as being upregulated in MYC amplified Group 3 medulloblastoma. Importantly, DFMO has been demonstrated to achieve high concentrations in brain tumors in a rat glioma model with minimal systemic toxicity. Based on this we hypothesize that DFMO would be attractive agent for Group 3 medulloblastoma treatment as it would inhibit both polyamine synthesis and LIN28B and potentially achieve high tumor concentrations. Here we demonstrate that treatment with increasing concentration of DFMO leads to significant reduction in Group 3 medulloblastoma viability, increased apoptosis and reduced levels of LIN28B and its downstream targets. We are currently investigating whether this drug can effectively inhibit in vivo tumor growth in orthotopic xenograft models of Group 3 medulloblastoma.
MDB-23. ELP1 GERMLINE DEFICIENCY SENSITIZES THE GRANULE NEURON LINEAGE TO SHH MEDULLOBLASTOMA AND EXPOSES NOVEL THERAPEUTIC VULNERABILITIES
Authors: Jesus Garcia-Lopez, Shiekh Tanveer Ahmad, Yiran Li, Brian Gudenas, Marija Kojic, Friedrik Manz, Barbara Jonchere, Anand Mayasundari, Aaron Pitre, Jennifer Hadley, Leena Paul, Melissa Batts, Stefan Pfister, Sebastian Waszak, Brandon Bianski, Christopher Tinkle, Brent Orr, Zoran Rankovic, Giles Robinson, Brandon Wainwright, Lena Kutscher, Hong Lin, Paul Northcott
Journal: Neuro-Oncology (2023)

Abstract Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB). ELP1 germline carriers develop SHH-MBs that exhibit coincident somatic PTCH1 mutations and universal loss-of-heterozygosity of the remaining ELP1 allele through chromosome 9q deletion. The molecular, biochemical, and cellular mechanisms by which germline ELP1/Elongator deficiency contribute to SHH-MB tumorigenesis remain largely unknown. Herein, we report that mice engineered to mimic germline Elp1 LOF (i.e., Elp1HET) seen in SHH-MB patients exhibit hallmark features of premalignancy events in cycling cerebellar granule neuron progenitors (GNPs), the lineage-of-origin for SHH-MB. Compared to wild-type counterparts, Elp1HET GNPs exhibit increased replication stress-associated DNA damage, homologous recombination-associated genomic instability, accelerated cell cycle kinetics, reduced p53-dependent apoptosis in response to genotoxic stress, and slowed differentiation. Orthotopic transplantation of Elp1HET GNPs harboring somatic Ptch1 inactivation into the cerebella of immunocompromised mice promotes onset of SHH-MB tumors with incomplete penetrance that exhibit reduced p53 transcriptional activity through a currently unknown mechanism(s). Concomitant Elp1 and Ptch1 gene targeting in p53-null GNPs reproduces highly penetrant cerebellar tumors recapitulating the molecular and phenotypic features of ELP1-associated SHH-MB. Finally, reactivation of the p53 pathway through preclinical treatment with an MDM2 inhibitor promotes cell death and prolongs the survival of patient-derived xenograft tumor (PDX) models harboring deleterious ELP1 mutations. Together, our findings reveal that germline Elp1 LOF heightens genomic instability and malignant transformation in cycling GNPs, providing a mechanistic model for the subgroup-restricted pattern of predisposition associated with pathogenic ELP1 germline carriers. These results provide essential mechanistic insight into the molecular and cellular basis of SHH-MB predisposition driven by ELP1 LOF and nominate therapies that overcome p53 pathway inhibition as a rational treatment option for affected children.
ATRT-17. CAR T CELL THERAPY TARGETING CLAUDIN-6 IS EFFECTIVE IN CELLULAR AND XENOGRAFT MODELS OF ATYPICAL TERATOID/RHABDOID TUMOR
Authors: Peter Madsen, Allison Stern, Conor Dickson, Cullen Wilson, Luke Patterson, Kyra Harvey, Crystal Griffin, Petra Oehm, Benjamin Rengstl, Carina Flemmig, Phillip Storm, Adam Resnick, Jessica Foster
Journal: Neuro-Oncology (2023)

Abstract Novel therapies are needed to for the treatment of atypical teratoid/rhabdoid tumor (ATRT), an aggressive brain tumor that predominantly affects young children and has an average 5-year survival under 50%. Claudin-6 (CLDN6) is a tight junction protein present during development and is expressed in up to 70% of ATRT specimens but not in normal tissue, making it a promising immunotherapeutic target. CLDN6-targeted chimeric antigen receptor (CAR) T cells in combination with a CAR T cell-amplifying mRNA vaccine have demonstrated antitumor activity against other CLDN6-expressing cancers in pre-clinical and a phase I adult trial (NCT04503278; Haanen J et al AACR, 2022). To assess the effectiveness of CLDN6-targeted CAR T cells against ATRT, we utilized a second-generation mRNA CAR with a 4-1BB costimulatory domain and single-chain variable fragment against CLDN6 (Reinhard et al, 2020). CLDN6 expression in patient-derived ATRT specimens was profiled by RNAseq (mean FPKM 11.4) and immunohistochemistry (positive staining in 53% of specimens). Tumor-derived cell lines were assessed for CLDN6 expression by flow cytometry. Co-culture of CLDN6-directed mRNA CAR T cells resulted in tumor-specific cytotoxicity compared to CD19-directed control CAR T cells in CLDN6-positive ATRT cell lines 7316-2187 (92% versus 15% at 10:1, p &amp;lt; 0.0001; 86% versus 0% at 5:1, p&amp;lt;0.0001) and 7316-2141 (75% versus 7% at 10:1, p&amp;lt;0.0001; 53% versus 0% at 5:1, p&amp;lt; 0.0001). Patient-derived, orthotopic xenograft ATRT models were created through intracranial injection of tumor cells into the cerebellum of NSG mice. Following engraftment with 7316-2141, repeated intratumoral administration of mRNA CLDN6 CAR T cells resulted in significant tumor regression (-1.9x108 vs. +2.4x109 p/sec/cm2/sr, p&amp;lt;0.001) and improved survival compared to mRNA CD19 CAR T cells (median OS not reached vs. 13 days, p=0.002). This work highlights the potential for targeting CLDN6 via CAR T cell therapy in patients with ATRT as a novel therapeutic strategy.
DIPG-51. ABDOMINAL METASTASES OF DIFFUSE MIDLINE GLIOMA, H3K27-ALTERED WITH A VENTRICULOPERITONEAL SHUNT
Authors: Margot Lazow, Kathleen Schieffer, Joshua Palmer, Ralph Salloum, Michelle Widemeyer, Eric Sribnick, Shiva Senthil Kumar, Banlanjo Umaru, Rachid Drissi, Elaine Mardis, Daniel Boué, Maryam Fouladi, Diana Thomas
Journal: Neuro-Oncology (2023)

Abstract Extraneural metastases are extremely rare in diffuse midline glioma (DMG), H3K27-altered, despite a tendency toward aggressive local growth and potential neuroaxis dissemination at progression. Ventriculoperitoneal shunt (VPS) placement for cerebrospinal fluid diversion is commonly performed in patients with thalamic tumors and increasingly considered in brainstem disease with developing hydrocephalus. Herein, we present a case of DMG seeding the abdomen presumably via the VPS. This patient was diagnosed at 22 years of age with a bithalamic tumor with extension into the brainstem and cerebellum as well as non-contiguous periventricular spread to the bilateral frontal lobes, with associated hydrocephalus. The patient underwent VPS insertion and biopsy, with pathology consistent with DMG, H3K27-altered. Whole exome sequencing revealed H3-3A and TP53 alterations as well as PDGFRA amplification. Treatment consisted of upfront craniospinal photon irradiation, with subsequent reduction in thalamic disease burden. Adjuvant therapy with an oral PDGFRA inhibitor (avapritinib) was initiated, though discontinued after two weeks due to worsening neurocognitive deficits. The patient presented three months post-completion of radiation, five months from diagnosis, and six weeks following VPS revision with rapidly progressive abdominal distension and altered mental status, with imaging demonstrating omental caking and significant malignant ascites, resulting in shunt malfunction and increased intracranial pressure. With limited therapeutic options, the family decided not to pursue further intervention and the patient died five days later. Autopsy confirmed metastatic disease throughout omentum, in addition to diffuse leptomeningeal dissemination. Comprehensive molecular profiling of diagnostic and post-mortem thalamic and omental tissue is in process to assess temporal as well as spatial genomic heterogeneity, including of metastasis-mediated pathways. In summary, abdominal dissemination of DMG, H3K27-altered is uncommon, but possible, especially in the presence of a VPS. Further research is necessary to determine biologic mechanisms and predictors of extraneural metastases in this disease.